Radiobiological Aspects of FLASH Radiotherapy

Abstract

Radiotherapy (RT) is one of the primary treatment modalities for cancer patients. The clinical use of RT requires a balance to be struck between tumor effect and the risk of toxicity. Sparing normal tissue is the cornerstone of reducing toxicity. Advances in physical targeting and dose-shaping technology have helped to achieve this. FLASH RT is a promising, novel treatment technique that seeks to exploit a potential normal tissue-sparing effect of ultra-high dose rate irradiation. A significant body of in vitro and in vivo data has highlighted a decrease in acute and late radiation toxicities, while preserving the radiation effect in tumor cells. The underlying biological mechanisms of FLASH RT, however, remain unclear. Three main mechanisms have been hypothesized to account for this differential FLASH RT effect between the tumor and healthy tissue: the oxygen depletion, the DNA damage, and the immune-mediated hypothesis. These hypotheses and molecular mechanisms have been evaluated both in vitro and in vivo. Furthermore, the effect of ultra-high dose rate radiation with extremely short delivery times on the dynamic tumor microenvironment involving circulating blood cells and immune cells in humans is essentially unknown. Therefore, while there is great interest in FLASH RT as a means of targeting tumors with the promise of an increased therapeutic ratio, evidence of a generalized FLASH effect in humans and data to show that FLASH in humans is safe and at least effective against tumors as standard photon RT is currently lacking. FLASH RT needs further preclinical investigation and well-designed in-human studies before it can be introduced into clinical practice.

FLASH Radiation Therapy — Key physical irradiation parameters and beam characteristics

“…A few non-exclusive hypotheses that have been put forward to justify the differential between healthy tissues and tumors in the FLASH effect will be thoroughly covered in this review work. These hypotheses are: oxygen depletion/Reactive Oxygen Species (ROS), DNA damage, Labile Iron Pool (LIP) availability, and immune-mediated [2,12,52,54]. FLASH irradiation at ultra-high dose rates has two direct and indirect impacts on tissues [12].…”

“…These hypotheses are: oxygen depletion/Reactive Oxygen Species (ROS), DNA damage, Labile Iron Pool (LIP) availability, and immune-mediated [2,12,52,54]. FLASH irradiation at ultra-high dose rates has two direct and indirect impacts on tissues [12]. In the indirect method, the cytotoxic superoxide anion and its protonated form, the hydroxyl radical, are produced as a result of the water radiolysis reaction (interaction of hydrated electrons (eaq ) and hydrogen radicals (H ) with oxygen molecules) and the generation of reactive oxygen species (ROS) (i.e., the hydroxyl radical) (see equation (2.1)) [7,12,55].…”

“…FLASH irradiation at ultra-high dose rates has two direct and indirect impacts on tissues [12]. In the indirect method, the cytotoxic superoxide anion and its protonated form, the hydroxyl radical, are produced as a result of the water radiolysis reaction (interaction of hydrated electrons (eaq ) and hydrogen radicals (H ) with oxygen molecules) and the generation of reactive oxygen species (ROS) (i.e., the hydroxyl radical) (see equation (2.1)) [7,12,55]. By attaching to DNA, the generated hydroxyl free radicals can damage it in a way that is simple to fix [7,12,52,56,57].…”

“…According to clinical data, the patient undergoing Conventional external beam Radiation Therapy (CONV-RT) typically receives 2 Gy fractions daily for five days a week for several weeks. The provided dose needs to be limited because of the destructive effect on nearby vital and healthy tissue [1,12]. The limited received dose may prevent a tumor from being completely eliminated and impair the efficiency of radiation [11].…”

Technical note: A small animal irradiation platform for investigating the dependence of the FLASH effect on electron beam parameters

“…Such investigation would also benefit ongoing research on FLASH mechanisms which, being dose rate dependent, are intrinsically linked to the structure of UHDR beams. More recently, additional biological mechanisms explaining the FLASH effect have been proposed, such as radical-radical recombination and differential DNA damage or immune responses between normal and tumor cells, [25][26][27] challenging the original transient oxygen depletion hypothesis. Unveiling the radiobiological mechanisms underpinning the FLASH effect is critical and would undoubtedly benefit ongoing and future clinical translations of FLASH radiotherapy.…”